JP2013518065A - Phenyl C-glucoside derivatives and their preparation and use - Google Patents

Abstract

の構造を有する化合物、並びにその薬学的に許容される塩及びプロドラッグエステルを提供する。The present invention relates to a sodium-glucose cotransporter 2 (SGLT2) inhibitor having a phenyl C-glucoside structure, a process for its preparation, a pharmaceutical composition containing it, and its use in the treatment of diabetes and the preparation of antidiabetic drugs. About. The present invention relates to general formula I
[Wherein R ⁵ and R ⁶ are defined as follows:
(1) R5 = R6 = Me, (2) R5 = Me, R6 = OMe, (3) R5 = Me, R6 = H, (4) R5 = Me, R6 = F, (5) R5 = F, R6 = H, and (6) R5 = OMe, R6 = H
Selected from]
[Chemical 1]

As well as pharmaceutically acceptable salts and prodrug esters thereof.

Description

  The present invention relates to the field of related drugs for diabetes. In particular, the present invention relates to a sodium-glucose cotransporter 2 (SGLT2) inhibitor having a phenyl C-glucoside structure, a preparation method thereof, and a pharmaceutical composition containing the same, which are effective for the treatment of diabetes. About.

  At present, there are 170 million diabetics worldwide, the majority of which are type II diabetics (ie non-insulin dependent). Currently, anti-diabetic drugs for clinical use mainly include metformin, sulfonylureas, insulin, thiazolidinediones, α-glucosidase inhibitors and dipeptidyl peptidase-IV inhibitors. Although these drugs are effective in treatment, there are safety concerns (eg, hepatotoxicity) in the case of long-term treatment, and some are thought to cause many problems such as weight gain.

  It has recently been discovered that sodium-glucose cotransporter 2 (SGLT2) is a new target for the treatment of diabetes. SGLT2 is mainly distributed in the proximal tubule of the kidney and plays a role of absorbing glucose in the urine and returning it to the blood. Therefore, inhibiting SGLT2 can result in a decrease in blood glucose concentration, thereby lowering blood glucose levels by a different route than the previous one. If the function of SGLT2 is inhibited, more glucose will be secreted into the urine, which allows diabetic patients to maintain normal blood glucose levels. Since SGLT2 inhibitors are not involved in glucose metabolism, they are thought to serve as an adjunct to the primary method for controlling blood glucose.

  Chinese Patent Application No. CN200610093189.9 includes the following structures as SGLT2 inhibitors:

[Wherein A is O, S, NH, (CH ₂ ) _n (where n = 0 to 3)]
Compounds having the formula are disclosed.

  Chinese Patent Application No. CN200380110040.1 includes the following structures as SGLT2 inhibitors:

[Wherein A is a covalent bond, O, S, NH, (CH ₂ ) _n (where n = 1 to 3)]
Compounds having the formula are disclosed.

  In Chinese Patent Application No. CN200480006761.2, SGLT2 inhibitors include the following structures:

[Wherein X is a covalent bond or a lower alkylene group]
Compounds having the formula are disclosed.

  In WO 2005/012326, SGLT2 inhibitor has the following structure:

Compounds having the formula are disclosed.

Chinese Patent Application No. CN200610093189.9 Chinese Patent Application No. CN200380110040.1 Chinese Patent Application No. CN200480006761.2 International Publication No. 2005/012326 Pamphlet

  In order to overcome the disadvantages and disadvantages of the prior art, one object of the present invention is to provide SGLT2 inhibitors with good activity, said inhibitors being phenyl C-glucosides having the structure of general formula I And pharmaceutically acceptable salts and prodrug esters thereof.

  Another object of the present invention is to provide a process for preparing phenyl C-glucosides having the structure of general formula I.

  Still another object of the present invention is to provide a compound of general formula I as an active ingredient or a pharmaceutically acceptable salt or prodrug ester thereof and one or more pharmaceutically acceptable carriers, excipients and And / or a pharmaceutical composition comprising a diluent and its use in the inhibition of sodium-glucose cotransporter 2, such as in the treatment of diabetes.

  The phenyl C-glucoside derivative provided by the present invention is a novel SGLT2 inhibitor that serves as a main component for preparing a medicament that can be further used for the treatment of diabetes, particularly non-insulin dependent diabetes.

  The invention will now be described in detail in conjunction with the objects of the invention.

  The present invention provides compounds having the structure of general formula I:

[Where:
R ¹ , R ² , R ³ and R ⁴ are H, F, Cl, Br, I, OH, OR ⁷ , SR ⁸ , OCF ₃ , CF ₃ , CHF ₂ , CH ₂ F, C ₁ -C ₃ alkyl. And cycloalkyl having 3 to 5 carbon atoms, wherein R ⁷ and R ⁸ are independently selected from C ₁ -C ₃ alkyl, wherein said alkyl and cycloalkyl are Both can be substituted with one or more atoms selected from F and Cl;
Ring A is selected from an aromatic monocycle and an aromatic bicycle, and the two rings in the aromatic bicycle are fused to form a condensed ring, or 2 It can be either covalently linked as two independent aromatic rings. Both the aromatic monocycle and the aromatic bicycle are 5- to 12-membered rings that can be substituted with 1 to 3 heteroatoms selected from O, S and N, and ring A can be any possible Can be linked to other parts of Compound I in position,
The definitions of R ⁵ and R ⁶ are as follows:
(1) R ⁵ = R ⁶ = Me,
(2) R ⁵ = Me, R ⁶ = OMe,
(3) R ⁵ = Me, R ⁶ = H,
(4) R ⁵ = Me, R ⁶ = F,
(5) R ⁵ = F, R ⁶ = H, and (6) R ⁵ = OMe, R ⁶ = H
Selected from].

Preferred compounds having the structure of general formula I are as follows:
[Where:
R ¹ , R ² , R ³ and R ⁴ are H, F, Cl, OR ⁷ , SR ⁸ , OCF ₃ , CF ₃ , CHF ₂ , CH ₂ F, C ₁ -C ₃ alkyl and 3-5 Independently selected from the group consisting of cycloalkyl having carbon atoms, wherein R ⁷ and R ⁸ are independently selected from C ₁ -C ₃ alkyl, wherein the aforementioned alkyl and cycloalkyl are both F atoms and Can be substituted with one or more atoms selected from Cl atoms,
Ring A is selected from an aromatic monocycle and an aromatic bicycle, and the two rings in the aromatic bicycle are fused to form a fused ring or are covalently bonded as two independent aromatic rings It can be either connected by. Both the aromatic monocycle and the aromatic bicycle are 5- to 12-membered rings that can be substituted with one or two heteroatoms selected from O and S, and ring A is in any possible position. Can be linked to other parts of Compound I with
The definitions of R ⁵ and R ⁶ are as follows:
(1) R ⁵ = R ⁶ = Me,
(2) R ⁵ = Me, R ⁶ = H,
(3) R ⁵ = Me, R ⁶ = F, and (4) R ⁵ = F, R ⁶ = H
Selected from].

More preferred compounds having the structure of general formula I are as follows:
[Where:
R ¹ , R ² , R ³ and R ⁴ are F, Cl, OR ⁷ , SR ⁸ , OCF ₃ , CF ₃ , CHF ₂ , CH ₂ F, C ₁ -C ₃ alkyl and 3 to 4 carbon atoms. Independently selected from the group consisting of cycloalkyl having the following: R ⁷ and R ⁸ are independently selected from C ₁ -C ₃ alkyl, wherein both alkyl and cycloalkyl are one or more Can be substituted with F atoms,
Ring A includes benzene, benzothiophene, benzofuran, azulene, benzene and thiophene rings connected in any possible form by a covalent bond, and benzene ring and furan connected in any possible form by a covalent bond Selected from the group consisting of rings, ring A can be linked to other parts of compound I at any possible position;
The definitions of R ⁵ and R ⁶ are as follows:
(1) R ⁵ = R ⁶ = Me,
(2) R ⁵ = Me, R ⁶ = H, and (3) R ⁵ = F, R ⁶ = H
Selected from].

  The structure of the most preferred compound having the structure of general formula I is as follows:

  The compounds of general formula I according to the invention comprise the following steps:

[Wherein base A can be selected from N-methylmorpholine, triethylamine, pyridine and 4-dimethylaminopyridine, base B can be selected from sodium acetate anhydride, pyridine and 4-dimethylaminopyridine, and base C is Can be selected from sodium methoxide, NaOH and KOH]
Can be synthesized.

In the foregoing synthesis step, the trimethylsilylating reagent may be trimethylchlorosilane, the alkyllithium reagent may be n-butyllithium, the acid may be selected from methanesulfonic acid and trifluoromethanesulfonic acid, and the Lewis acid is BF. ₃ · Et ₂ O, BF ₃ · MeCN and trifluoroacetic acid can be selected, the reducing agent can be selected from triethylsilane and triisopropylsilane, and the acetylating reagent can be selected from acetic anhydride and acetyl chloride.

  Compound II is treated with a trimethylsilylating reagent in the presence of a base to yield compound III. The base is N-methylmorpholine, triethylamine, pyridine, 4-dimethylaminopyridine and the like, and the trimethylsilylating reagent is trimethylchlorosilane and the like.

Compound IV is treated with an alkyl lithium reagent such as n-butyllithium to yield compound V, which is not isolated, but reacts directly with compound II in the reaction mixture to yield compound VI. Compound VI is treated with methanol under the catalysis of acids such as methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid to yield compound VII. Compound _{VII, BF 3 · Et 2 O} , in the presence of a Lewis acid such as _BF 3 _· MeCN or trifluoroacetic acid, triethylsilane, and Compound VIII is reduced by a reducing agent such as triisopropylsilane. Compound VIII is acetylated to IX with one of acetic anhydride, acetyl chloride, etc. in the presence of a base such as sodium acetate anhydride, pyridine and 4-dimethylaminopyridine. Compound IX is subjected to column chromatography or recrystallization to give compound X. Compound X is treated with a base such as sodium methoxide, NaOH, KOH to remove acetyl to yield Compound I.

  In particular, the compounds of general formula I according to the invention have the following steps:

Is synthesized.

Compound IV can be prepared by the following different routes, depending on the choice of R ⁵ and R ⁶ .

(1) R ⁵ = R ⁶ = Me
In this case, compound IV can be represented as compound IV-1.

  Compound IV-1 has the following route:

Is synthesized.

  Compound XVIII is treated with a reagent such as MeLi, MeMgI or MeMgBr to yield compound XIX. Compound XIX reacts with compound XII in the presence of an acid such as methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid or concentrated sulfuric acid to give compound IV-1.

(2) R ⁵ = Me, R ⁶ = OMe
In this case, compound IV can be represented as compound IV-2.

  Compound IV-2 has the following pathway:

Is synthesized.

Compound XIII is treated with a reagent such as MeLi, MeMgI or MeMgBr to yield compound XX. Compound XX is treated with a methylating reagent such as Me ₂ SO ₄ or MeI in the presence of a base such as NaH, KH or NaNH ₂ to yield compound IV-2.

  Alternatively, compound XX in the above-described pathway can be obtained by the following method:

Can be synthesized.

  Compound XIV is treated with n-BuLi or Mg metal to yield compound XV. Compound XV reacts with compound XXI to yield compound XX.

(3) R ⁵ = Me, R ⁶ = H
In this case, compound IV can be represented as compound IV-3.

  Compound IV-3 has the following pathway:

Is synthesized.

Compound XX is reduced to compound IV-3 with a reducing agent such as triethylsilane or triisopropylsilane in the presence of an acid such as BF ₃ .Et ₂ O or trifluoroacetic acid.

(4) R ⁵ = Me, R ⁶ = F
In this case, compound IV can be represented as compound IV-4.

  Compound IV-4 has the following route:

Is synthesized.

Compound XX reacts with a fluorinating agent such as SF ₄ or Et ₂ NSF ₃ to yield compound IV-4.

(5) R ⁵ = F, R ⁶ = H
In this case, compound IV can be represented as compound IV-5.

  Compound IV-5 has the following route:

Is synthesized.

Compound XVII is reacted with a fluorinating agent such as SF ₄ or _Et 2 NSF _3, to give a compound IV-5.

Compound XVII can be produced by reducing compound XIII with a reducing agent selected from NaBH ₄ , KBH ₄ , LiAlH _4, LiBH _{4 and the} like.

(6) R ⁵ = OMe, R ⁶ = H
In this case, compound IV can be represented as compound IV-6.

  Compound IV-6 has the following route:

Is synthesized.

Compound XVII is treated with a methylating reagent such as Me ₂ SO ₄ or MeI in the presence of a base such as NaH, KH or NaNH ₂ to yield compound IV-6.

  The pharmaceutically acceptable prodrug esters of the compounds of general formula I of the present invention may be any acetyl, pivaloyl, one of a variety of phosphoryls, carbamoyl, and any one or more hydroxyl groups present in the molecule. And esters formed by esterification with alkoxyformyl and the like.

  A pharmaceutical composition may be prepared by combining a compound of general formula I of the present invention with one or more pharmaceutically acceptable carriers, excipients or diluents. This pharmaceutical composition may be formulated into a solid oral preparation, liquid oral preparation, injectable preparation, and the like. The solid oral preparation and liquid oral preparation include tablets, dispersible tablets, sugar-coated preparations, granules, dry powders, capsules and liquids. Injectable preparations include vial injections, infusion solutions, lyophilized powder injections, and the like.

  The pharmaceutically acceptable auxiliary materials of the composition of the present invention include fillers, disintegrants, lubricants, lubricants, foaming agents, correctives, preservatives, coating materials or other excipients. Selected.

  Fillers include one or more of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrophosphate, calcium sulfate, calcium carbonate and microcrystalline cellulose. May be. The adhesive may include one or more of sucrose, starch, povidone, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyethylene glycol, pharmaceutical ethanol and water. Disintegrants may include one or more of starch, crospovidone, croscarmellose sodium, low substituted hydroxypropylcellulose, sodium carboxymethylcellulose and effervescent disintegrants.

  The compounds of general formula I according to the invention are effective in inhibiting SGLT2 and can be used as active ingredients in the preparation of a medicament for treating diabetes. The activity of the compounds of general formula I according to the invention is confirmed in vivo by a hypoglycemia model.

  The compounds of general formula I are effective over a very wide dosage range. For example, the daily dose may be 1 mg to 1000 mg per person and can be administered in single or multiple dose forms. The actual dosage for ingesting the compound of general formula I can be determined by the physician in view of the relevant conditions. Such conditions include the subject's body condition, route of administration, age, weight, personal response to medication, severity of symptoms, and the like.

Embodiments of the Invention The following section further describes the invention in conjunction with the examples. It should be understood that the following examples are intended to illustrate the present invention and not to limit the present invention. Various modifications that can be made by those skilled in the art in light of the teachings of the present invention should be covered by the protection scope claimed by the claims of this application.
[Example 1]

  1- {4-Chloro-3-[(4-ethoxyphenyl) fluoromethyl] phenyl} -1-deoxy-β-D-glucopyranose

A. (5-Bromo-2-chlorophenyl) (4-ethoxyphenyl) fluoromethane 2.35 g 5-bromo-2-chlorobenzoic acid, 1.40 g oxalyl chloride and 5 ml anhydrous dichloromethane in a 100 ml round bottom flask. In addition, magnetic stirring was performed at room temperature. A drop of N, N-dimethylformamide was added therein. The mixture was stirred overnight at room temperature and then the solvent was evaporated on a rotary evaporator. The resulting residue was dissolved in 5 ml anhydrous dichloromethane and 1.34 g phenetole was added. The resulting mixture was magnetically stirred in an ice-water bath before 1.73 g of aluminum chloride was added slowly in small portions, after which the reaction mixture was stirred at room temperature for an additional 2 hours. The reaction mixture was then carefully poured into ice water, stirred and extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator. The resulting mixture was purified by column chromatography to give colorless crystals, which was (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone. ^{ESI-MS, m / z =} 339.3 ([M (79 Br) +1]), 341.2 ([M (81 Br) +1]).

3.40 g of (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone prepared as described above and 20 ml of anhydrous THF were added into a 100 ml round bottom flask and stirred in an ice water bath. 0.38 g of LiAlH ₄ was added in portions, after which the resulting mixture was stirred for an additional hour. The reaction mixture was carefully poured into 200 ml of ice water and then adjusted to pH 2-3 with concentrated hydrochloric acid. The resulting acidic mixture was extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give an off-white solid, which was (5-bromo-2-chlorophenyl) (4 -Ethoxyphenyl) methanol. ^{ESI-MS, m / z =} 341.1 ([M (79 Br) +1]), 343.3 ([M (81 Br) +1]).

3.07 g of (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanol prepared as described above was dissolved in 10 ml of anhydrous dichloromethane and then 5 ml of (diethylamino) sulfur trifluoride (Et ₂ NSF ₃ ) Was added. The reaction mixture was stirred at room temperature overnight, poured into 200 ml ice water and then extracted twice with 100 ml dichloromethane. The combined extracts were washed with saturated NaCl solution and dried over anhydrous sodium sulfate to give a colorless oily product after removal of the solvent on a rotary evaporator. A colorless oily product was obtained after purification by silica column chromatography, which was (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) fluoromethane. ^{ESI-MS, m / z =} 343.2 ([M (79 Br) +1]), 345.3 ([M (81 Br) +1]).

B. 1- {4-Chloro-3-[(4-ethoxyphenyl) fluoromethyl] phenyl} -1-deoxy-β-D-glucopyranose (5-Bromo-2-chlorophenyl) (4- Ethoxyphenyl) fluoromethane (2.72 g), 10 ml anhydrous THF and a magnetic stir bar were added into a 100 ml round bottom flask. The flask was sealed with a rubber septum, placed in an acetone-dry ice system and cooled to -78 ° C. While stirring, 8 ml (1.0 M) of n-BuLi was slowly added into the reaction mixture via syringe, after which the mixture was stirred at −78 ° C. for an additional hour before the Example in 10 ml of dry toluene. The solution of 2,3,4,6-tetra-O-trimethylsilylgluconolactone prepared in 1 was slowly added into the reaction mixture via syringe. After the addition, the mixture was stirred for an additional hour, then a solution of 1.92 g methanesulfonic acid dissolved in 10 ml anhydrous toluene was added dropwise via syringe, then the mixture was allowed to warm to room temperature and overnight at room temperature. Stir. The reaction mixture was poured into saturated NaCl solution and extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was methyl 1- {4-chloro-3 -[(4-Ethoxyphenyl) fluoromethyl] phenyl}-[alpha] / [beta] -D-glucopyranoside, ESI-MS, m / z = 457.1 ([M + 1]).

  The resulting methyl 1- {4-chloro-3-[(4-ethoxyphenyl) fluoromethyl] phenyl} -α / β-D-glucopyranoside (3.07 g) was dissolved in 3 ml of anhydrous dichloromethane and placed in an ice-water bath. Then, 2 ml of triethylsilane and 1 ml of boron trifluoride diethyl etherate were added successively. The reaction mixture was stirred at room temperature overnight, poured carefully into 100 ml ice water, adjusted to pH = 8 with saturated sodium bicarbonate solution and extracted twice with 100 ml dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was 1- {4-chloro-3- [ (4-Ethoxyphenyl) fluoromethyl] phenyl} -α / β-D-glucopyranose, ESI-MS, m / z = 427.4 ([M + 1]).

  2.57 g of the resulting 1- {4-chloro-3-[(4-ethoxyphenyl) fluoromethyl] phenyl} -α / β-D-glucopyranose colorless oily product was added to 20 ml of acetic anhydride. And 0.5 g of sodium acetate anhydrous was added therein. The resulting solution was magnetically stirred and heated to reflux for 1 hour. After cooling, the mixture was poured into 100 ml water, stirred at room temperature overnight and extracted twice with 100 ml dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give an off-white solid. Colorless crystals formed after purification by silica column chromatography, which were 2,3,4,6-tetra-O-acetyl-1- {4-chloro-3-[(4-ethoxyphenyl) fluoromethyl] phenyl. } -1-deoxy-β-D-glucopyranose, ESI-MS, m / z = 595.2 ([M + 1]).

2.86 g of the aforementioned 2,3,4,6-tetra-O-acetyl-1- {4-chloro-3-[(4-ethoxyphenyl) fluoromethyl] phenyl} -1-deoxy-β-D- Glucopyranose was dissolved in 7 ml of anhydrous methanol containing 0.11 g of sodium methoxide and stirred at room temperature for 5 hours. Then 1 g of dry strongly acidic resin was added and stirred at room temperature overnight. The resin is removed by filtration and the resulting filtrate is evaporated to dryness on a rotary evaporator to give a white solid which is 1- {4-chloro-3-[(4-ethoxyphenyl) fluoromethyl] phenyl} -1-deoxy-β-D-glucopyranose, ESI-MS, m / z = 427.2 ([M + 1]).
[Example 2-15]

It can be appreciated that the compounds listed in the following table can be made using the methods and processes of Example 1 but varying R ¹ , R ² , R ³ , R ⁴ and Ring A.

［実施例１６］

[Example 16]

  1- {4-Chloro-3-[(dimethyl) (4-ethoxyphenyl) methyl] phenyl} -1-deoxy-β-D-glucopyranose

A. (5-Bromo-2-chlorophenyl) (4-ethoxyphenyl) (dimethyl) methane 2.64 g ethyl 5-bromo-2-chlorobenzoic acid and 10 ml anhydrous THF were added into a 100 ml round bottom flask and the result The resulting solution is cooled in an ice-water bath, magnetically stirred, and then, using a pressure-equalizing funnel, 25 ml (1.0 M) of methyl iodine magnesium in THF. Was added. After the addition, the reaction mixture was stirred at room temperature for 1 hour, carefully poured into 200 ml ice water and adjusted to pH = 3-4 with concentrated hydrochloric acid. The resulting acidic mixture was extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was (5-bromo-2-chlorophenyl) Dimethylmethanol. ¹ H NMR (DMSO-d ₆ , 400 MHz), δ 7.95 (d, 1H, J = 2.8 Hz), 7.44 (dd, 1H, J = 2.6 Hz and 8.6 Hz), 7.33 (d, 1H, J = 8.0Hz ), 5.46 (s, 1H), 1.56 (s, 6H); ESI-MS, m / z = 249.2 ([M (79 Br) +1] ^{), 251.3 ([M (81} Br) +1]).

2.35 g of the aforementioned (5-bromo-2-chlorophenyl) dimethylmethanol and 2.44 g (20 mmol) of phenetole are added into a 25 ml round bottom flask and magnetically stirred before 4.11 g of aluminum chloride anhydride. Was added. The reaction mixture was stirred at 20 ° C. overnight and carefully poured into 200 ml ice water. The resulting acidic mixture was extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was 2.69 g of (5-bromo- 2-chlorophenyl) (4-ethoxyphenyl) (dimethyl) methane. The yield was 81%. ¹ H NMR (DMSO-d ₆ , 400 MHz), δ 7.76 (d, 1H, J = 2.4 Hz), 7.47 (dd, 1H, J = 2.4 Hz and 8.4 Hz), 7.25 (D, 1H, J = 8.4 Hz), 6.96 (d, 2H, J = 8.8 Hz), 6.78 (d, 2H, J = 9.2 Hz), 3.96 (q, 2H, J = 7.1Hz), 1.64 (s , 6H), 1.29 (t, 3H, J = 7.0Hz); ESI-MS, m / z = 353.4 ([M (79 Br) +1 ^{]), 355.2 ([M (} 81 Br) +1]).

B. 1- {4-Chloro-3-[(dimethyl) (4-ethoxyphenyl) methyl] phenyl} -1-deoxy-β-D-glucopyranose (5-Bromo-2-chlorophenyl) ( 4-Ethoxyphenyl) dimethylmethane 2.69 g, 10 ml anhydrous THF and a magnetic stir bar were added into a 100 ml round bottom flask. The flask was sealed with a rubber septum, placed in an acetone-dry ice system and cooled to -78 ° C. While stirring, 8 ml (1.0 M) of n-BuLi was slowly added into the reaction mixture via syringe, after which the mixture was stirred at −78 ° C. for an additional hour before the Example in 10 ml of anhydrous toluene. A solution of 2,3,4,6-tetra-O-trimethylsilylgluconolactone as prepared in 1 was slowly added into the reaction mixture via syringe. After the addition, the mixture was stirred for an additional hour, then a solution of 1.92 g methanesulfonic acid in 10 ml anhydrous methanol was added via syringe, then the mixture was warmed to room temperature and stirred overnight at room temperature. The reaction mixture was poured into saturated NaCl solution and extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was 1- {4-chloro-3- [(Dimethyl) (4-ethoxyphenyl) methyl] phenyl} -α / β-D-methylglucopyranoside, ESI-MS, m / z = 467.1 ([M + 1]).

  The resulting methyl 1- {4-chloro-3-[(dimethyl) (4-ethoxyphenyl) methyl] phenyl} -α / β-D-glucopyranoside (3.09 g) was dissolved in 3 ml of anhydrous dichloromethane, After stirring in the bath, 2 ml of triethylsilane and 1 ml of boron trifluoride diethyl etherate were added successively. The resulting reaction mixture was stirred at room temperature overnight, carefully poured into 100 ml ice water, adjusted to pH = 8 with saturated sodium bicarbonate solution and extracted twice with 100 ml dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was 1- {4-chloro-3- [(Dimethyl) (4-ethoxyphenyl) methyl] phenyl} -α / β-D-glucopyranose, ESI-MS, m / z = 437.2 ([M + 1]).

The resulting colorless oily product 1- {4-chloro-3-[(dimethyl) (4-ethoxyphenyl) methyl] phenyl} -α / β-D-glucopyranose 2.62 g was added to 20 ml anhydrous Dissolved in acetic acid and added 0.5 g sodium acetate anhydride. The resulting solution was magnetically stirred and heated to reflux for 1 hour. After cooling, the mixture was poured into 100 ml water, stirred at room temperature overnight and extracted twice with 100 ml dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give an off-white solid. Colorless crystals formed after purification by silica column chromatography, which were 2,3,4,6-tetra-O-acetyl-1- {4-chloro-3-[(4-ethoxyphenyl) methyl] phenyl} It was -1-deoxy-β-D-glucopyranose. ¹ H NMR (DMSO-d ₆ , 400 MHz), δ 7.58 (s, 1H), 7.27 (s, 2H), 6.90 (d, 2H, J = 8.8 Hz), 6.76 ( d, 2H, J = 8.8 Hz), 5.39 (t, 1H, J = 9.6 Hz), 5.13 (t, 1H, J = 9.6 Hz), 5.05 (t, 1H, J = 9.6 Hz), 4.78 (d, 1H, J = 9.6 Hz), 4.14 to 4.15 (m, 2H), 4.06 to 4.11 (m, 1H), 3.95. (Q, 2H, J = 6.9 Hz), 2.02 (s, 3H), 2.01 (s, 3H), 1.94 (s, 3H), 1.82 (s, 3H), 1. 64 (s, 6H), 1.28 (t, 3H, J = 7.0 Hz); ESI-MS, m / z = 605.3 ([M + 1]).

2,3,4,6-Tetra-O-acetyl-1- {4-chloro-3-[(4-ethoxyphenyl) methyl] phenyl} -1-deoxy-β-D-glucose prepared as described above 3.27 g of pyranose was dissolved in 7 ml of anhydrous methanol containing 0.11 g of sodium methoxide and stirred at room temperature for 5 hours, then 1 g of dry strong acidic resin was added and stirred at room temperature overnight. The resin is removed by filtration and the resulting filtrate is evaporated to dryness on a rotary evaporator to give a white solid which is 1- {4-chloro-3-[(dimethyl) (4-ethoxyphenyl) methyl] Phenyl} -1-deoxy-β-D-glucopyranose. ¹ H NMR (DMSO-d ₆ , 400 MHz), δ 7.62 (s, 1H), 7.23 (s, 2H), 6.97 (d, 2H, J = 8.8 Hz), 6.76 ( d, 2H, J = 8.8 Hz), 4.93 to 4.95 (m, 2H), 4.87 (d, 1H, J = 5.6 Hz), 4.46 (t, 1H, J = 5) .8 Hz), 4.09 (d, 1 H, J = 9.6 Hz), 3.95 (q, 2 H, J = 6.9 Hz), 3.71 to 3.75 (m, 1 H), 3.44 To 3.50 (m, 1H), 3.24 to 3.30 (m, 2H), 3.15 to 3.22 (m, 2H), 1.653 (s, 3H), 1.645 (s) , 3H), 1.29 (t, 3H, J = 7.0 Hz); ESI-MS, m / z = 437.4 ([M + 1]).
[Examples 17-35]

It can be appreciated that the compounds listed in the table below can be made using the methods and processes of Example 16 but varying R ¹ , R ² , R ³ , R ⁴ and Ring A.

［実施例３６］

[Example 36]

  1- {4-Chloro-3- [1- (4-ethoxyphenyl) ethyl] phenyl} -1-deoxy-β-D-glucopyranose

A. 1- (5-bromo-2-chlorophenyl) -1- (4-ethoxyphenyl) ethane 3.40 g of (5-bromo-2-chlorophenyl) -1- (4-ethoxyphenyl) ketone and 10 ml of anhydrous THF. To a 100 ml round bottom flask, the resulting solution was cooled in an ice-water bath and magnetically stirred before adding 10 ml (1.0 M) of methyl magnesium iodide in THF with an isobaric dropping funnel. . After the addition, the reaction mixture was stirred at room temperature for 1 hour, carefully poured into 200 ml ice water and adjusted to pH = 3-4 with concentrated hydrochloric acid. The resulting acidic mixture was extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was 1- (5-bromo-2-chlorophenyl ) -1- (4-Ethoxyphenyl) ethanol. ^{ESI-MS, m / z =} 355.2 ([M (79 Br) +1]), 357.2 ([M (81 Br) +1]).

3.20 g of the aforementioned 1- (5-bromo-2-chlorophenyl) -1- (4-ethoxyphenyl) ethanol was added into a 25 ml round bottom flask and dissolved in 3 ml of anhydrous dichloromethane and magnetically stirred. Next, 2 ml of triethylsilane and 1 ml of boron trifluoride diethyl etherate were added continuously. The reaction mixture was stirred at room temperature overnight and then carefully poured into 200 ml of ice water. The resulting acidic mixture was extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was 1- (5-bromo-2-chlorophenyl ) -1- (4-Ethoxyphenyl) ethane. ^{ESI-MS, m / z =} 339.2 ([M (79 Br) +1]), 341.3 ([M (81 Br) +1]).

B. 1- {4-Chloro-3- [1- (4-ethoxyphenyl) ethyl] phenyl} -1-deoxy-β-D-glucopyranose 1- (5-bromo-2-chlorophenyl) prepared as described above 2.45 g of -1- (4-ethoxyphenyl) ethane, 10 ml of anhydrous THF and a magnetic stir bar were added into a 100 ml round bottom flask. The flask was sealed with a rubber septum, placed in an acetone-dry ice system and cooled to -78 ° C. During stirring, 8 ml (1.0 M) of n-BuLi was slowly added into the reaction vessel via syringe, after which the reaction was stirred at −78 ° C. for an additional hour before performing in 10 ml of anhydrous toluene. A solution of 2,3,4,6-tetra-O-trimethylsilylgluconolactone as prepared in Example 1 was slowly added into the reaction mixture via syringe. After the addition, the mixture was stirred for an additional hour, then a solution of 1.92 g methanesulfonic acid in 10 ml anhydrous methanol was added via syringe and the mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was poured into saturated NaCl solution and extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was methyl 1- {4-chloro-3 -[1- (4-Ethoxyphenyl) ethyl] phenyl}-[alpha] / [beta] -D-glucopyranoside, ESI-MS, m / z = 453.4 ([M + 1]).

  The resulting oily product methyl 1- {4-chloro-3- [1- (4-ethoxyphenyl) ethyl] phenyl} -α / β-D-glucopyranoside 2.77 g was dissolved in 3 ml of anhydrous dichloromethane. And stirred in an ice-water bath, then 2 ml of triethylsilane and 1 ml of boron trifluoride diethyl etherate were added successively. The reaction mixture was stirred at room temperature overnight, poured carefully into 100 ml ice water, adjusted to pH = 8 with saturated sodium bicarbonate solution and extracted twice with 100 ml dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was 1- {4-chloro-3- [1- (4-Ethoxyphenyl) ethyl] phenyl} -α / β-D-glucopyranose, ESI-MS, m / z = 423.2 ([M + 1]).

  The resulting colorless oily product 1- {4-chloro-3- [1- (4-ethoxyphenyl) ethyl] phenyl} -α / β-D-glucopyranose (2.32 g) was added to 20 ml of acetic anhydride. And 0.5 g of anhydrous sodium acetate was added. The resulting solution was magnetically stirred and heated to reflux for 1 hour. After cooling, the mixture was poured into 100 ml water, stirred at room temperature overnight and then extracted twice with 100 ml dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give an off-white solid. Colorless crystals formed after purification by silica column chromatography, which were 2,3,4,6-tetra-O-acetyl-1- {4-chloro-3- [1- (4-ethoxyphenyl) ethyl] Phenyl} -1-deoxy-β-D-glucopyranose. ESI-MS, m / z = 591.4 ([M + 1]).

3.12 g of the aforementioned 2,3,4,6-tetra-O-acetyl-1- {4-chloro-3- [1- (4-ethoxyphenyl) ethyl] phenyl} -1-deoxy-β-D -Glucopyranose was dissolved in 7 ml anhydrous methanol containing 0.11 g sodium methoxide and stirred at room temperature for 5 hours, then 1 g dry strong acidic resin was added and stirred overnight at room temperature. The resin is removed by filtration and the resulting filtrate is evaporated to dryness on a rotary evaporator to give a white solid which is 1- {4-chloro-3- [1- (4-ethoxyphenyl) ethyl] phenyl. } -1-deoxy-β-D-glucopyranose, ESI-MS, m / z = 423.2 ([M + 1]); ¹ H NMR (DMSO-d ₆ , 400 MHz), δ 7.30- 7.38 (m, 2H), 7.20 to 7.22 (d, 1H, J = 8.4 Hz), 7.08 to 7.11 (m, 2H), 6.79 to 6.82 (m , 2H), 4.43 to 4.48 (m, 1H), 3.93 to 4.03 (m, 3H), 3.68 to 3.70 (d, 1H, J = 11.6 Hz), 3 .42-3.46 (m, 1H), 3.07-3.29 (m, 4H), 1.52-1 .53 (d, 3H, J = 6.8 Hz), 1.27 to 1.30 (t, 3H, J = 7.0 Hz).
[Examples 37-50]

It can be appreciated that the methods and processes of Example 36 can be used, but varying R ¹ , R ² , R ³ , R ⁴ and Ring A can produce the compounds listed in the table below.

［実施例５１］

[Example 51]

  1- {4-Chloro-3- [1- (4-ethoxyphenyl) -1-methoxyethyl] phenyl} -1-deoxy-β-D-glucopyranose

A. 1- (5-Bromo-2-chlorophenyl) -1- (4-ethoxyphenyl) -1-methoxyethane 3.40 g of (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) (methyl) methanol and 10 ml Of anhydrous THF was added into a 100 ml round bottom flask and the resulting solution was cooled in an ice-water bath and magnetically stirred. 0.40 g (60%) of solid NaH was added in portions, after which the resulting mixture was stirred for an additional hour before adding 1.70 g of dry MeI. The reaction mixture was stirred at room temperature overnight, carefully poured into 200 ml of ice water and then the pH was adjusted to 2-3 with concentrated hydrochloric acid. The resulting acid mixture was extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was 1- (5-bromo-2- Chlorophenyl) -1- (4-ethoxyphenyl) -1-methoxyethane. ^{ESI-MS, m / z =} 369.2 ([M (79 Br) +1]), 371.4 ([M (81 Br) +1]).

B. 1- {4-Chloro-3- [1- (4-ethoxyphenyl) -1-methoxy-ethyl] phenyl} -1-deoxy-β-D-glucopyranose 1- (5-bromo prepared as described above 2-Chlorophenyl) -1- (4-ethoxyphenyl) -1-methoxyethane 3.40 g, 10 ml anhydrous THF and a magnetic stir bar were added to a 100 ml round bottom flask. The flask was sealed with a rubber septum, placed in an acetone-dry ice system and cooled to -78 ° C. During stirring, 10 ml (1.0 M) of n-BuLi was slowly added into the reaction mixture via syringe, after which the mixture was stirred at −78 ° C. for an additional hour before the Example in 10 ml of anhydrous toluene. A solution of 2,3,4,6-tetra-O-trimethylsilylgluconolactone as prepared in 1 was slowly added into the reaction mixture via syringe. After the addition, the mixture was stirred for an additional hour and a solution of 1.92 g methanesulfonic acid in 10 ml anhydrous methanol was added via syringe, and then the mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was poured into saturated NaCl solution and extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was methyl 1- {4-chloro-3 -[1- (4-Ethoxyphenyl) -1-methoxymethyl] phenyl}-[alpha] / [beta] -D-glucopyranoside, ESI-MS, m / z = 483.4 ([M + 1]).

  3.69 g of the resulting methyl 1- {4-chloro-3- [1- (4-ethoxyphenyl) -1-methoxy-ethyl] phenyl} -α / β-D-glucopyranoside was added to 3 ml of anhydrous dichloromethane. After dissolving and stirring in an ice-water bath, 2 ml of triethylsilane and 1 ml of boron trifluoride diethyl etherate were added successively. The reaction mixture was stirred at room temperature overnight, poured carefully into 100 ml ice water, adjusted to pH = 8 with saturated sodium bicarbonate solution and extracted twice with 100 ml dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was 1- {4-chloro-3- [1- (4-Ethoxyphenyl) -1-methoxyethyl] phenyl} -α / β-D-glucopyranose, ESI-MS, m / z = 453.4 ([M + 1]).

  The resulting oily product 1- {4-chloro-3- [1- (4-ethoxyphenyl) -1-methoxyethyl] phenyl} -α / β-D-glucopyranose (3.13 g) in 20 ml Dissolved in acetic anhydride and added 0.5 g sodium acetate anhydride. The resulting solution was magnetically stirred and heated to reflux for 1 hour. After cooling, the mixture was poured into 100 ml water, stirred at room temperature overnight and extracted twice with 100 ml dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give an off-white solid. Colorless crystals formed after purification by silica column chromatography, which were 2,3,4,6-tetra-O-acetyl-1- {4-chloro-3-[(4-ethoxyphenyl) -1-methoxy. Ethyl] phenyl} -1-deoxy-β-D-glucopyranose. ESI-MS, m / z = 621.4 ([M + 1]).

4.07 g of the aforementioned 2,3,4,6-tetra-O-acetyl-1- {4-chloro-3- [1- (4-ethoxyphenyl) -1-methoxyethyl] phenyl} -1-deoxy -Β-D-Glucopyranose was dissolved in 7 ml of anhydrous methanol containing 0.11 g of sodium methoxide and stirred at room temperature for 5 hours. Then 1 g of dry strongly acidic resin was added and stirred at room temperature overnight. The resin is removed by filtration and the resulting filtrate is evaporated to dryness on a rotary evaporator to give a white solid which is 1- {4-chloro-3- [1- (4-ethoxyphenyl) -1- Methoxyethyl] phenyl} -1-deoxy-β-D-glucopyranose. ESI-MS, m / z = 453.4 ([M + 1]).
[Example 52]

  1- {4-Chloro-3- [1- (4-ethoxyphenyl) -1-fluoroethyl] phenyl} -1-deoxy-β-D-glucopyranose

A. 1- (5-Bromo-2-chlorophenyl) -1- (4-ethoxyphenyl) -1-fluoroethane (5-Bromo-2-chlorophenyl) (4-ethoxyphenyl) (methyl) methanol prepared according to Example 36 3.56 g and 10 ml of anhydrous dichloromethane were added to a 100 ml round bottom flask. The resulting solution was cooled in an ice water bath and magnetically stirred before adding ₂ ml of (diethylamino) sulfur trifluoride (Et ₂ NSF ₃ ) and then stirring the reaction mixture overnight before adding 200 ml. Carefully poured into the ice water. The resulting mixture was extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was 1- (5-bromo-2- Chlorophenyl) -1- (4-ethoxyphenyl) -1-fluoroethane. ^{ESI-MS, m / z =} 357.3 ([M (79 Br) +1]), 359.1 ([M (81 Br) +1]).

B. 1- {4-Chloro-3- [1- (4-ethoxyphenyl) -1-fluoroethyl] phenyl} -1-deoxy-β-D-glucopyranose 1- (5-Bromo-, prepared as described above 2-Chlorophenyl) -1- (4-ethoxyphenyl) -1-fluoroethane 3.40 g, 10 ml anhydrous THF and a magnetic stir bar were added to a 100 ml round bottom flask. The flask was sealed with a rubber septum, placed in an acetone-dry ice system and cooled to -78 ° C. During stirring, 10 ml (1.0 M) of n-BuLi was slowly added into the reaction vessel via syringe, after which the mixture was stirred at −78 ° C. for an additional hour before the Example in 10 ml of anhydrous toluene. A solution of 2,3,4,6-tetra-O-trimethylsilylgluconolactone as prepared in 1 was slowly added into the reaction mixture via syringe. After the addition, the mixture was stirred for an additional hour, then a solution of 1.92 g methanesulfonic acid in 10 ml anhydrous methanol was added via syringe, and then the mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was poured into saturated NaCl solution and extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was methyl 1- {4-chloro-3 -[1- (4-Ethoxyphenyl) -1-fluoroethyl] phenyl}-[alpha] / [beta] -D-glucopyranoside, ESI-MS, m / z = 471.3 ([M + 1]).

  The resulting methyl 1- {4-chloro-3- [1- (4-ethoxyphenyl) -1-fluoroethyl] phenyl} -α / β-D-glucopyranoside 3.58 g is dissolved in 3 ml of anhydrous dichloromethane. And stirred in an ice-water bath, then 2 ml of triethylsilane and 1 ml of boron trifluoride diethyl etherate were added successively. The reaction mixture was stirred at room temperature overnight, poured carefully into 100 ml ice water, adjusted to pH = 8 with saturated sodium bicarbonate solution and extracted twice with 100 ml dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was 1- {4-chloro-3- It was [1- (4-ethoxyphenyl) -1-fluoroethyl] phenyl} -α / β-D-glucopyranose. ESI-MS, m / z = 441.2 ([M + 1]).

  The resulting colorless oily product 1- {4-chloro-3- [1- (4-ethoxyphenyl) -1-fluoroethyl] phenyl} -α / β-D-glucopyranose After dissolving in 20 ml of acetic anhydride, 0.5 g of sodium acetate anhydride was added. The resulting solution was magnetically stirred and heated to reflux for 1 hour. After cooling, the mixture was poured into 100 ml water, stirred at room temperature overnight and extracted twice with 100 ml dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give an off-white solid. Colorless crystals formed after purification by silica column chromatography, which were 2,3,4,6-tetra-O-acetyl-1- {4-chloro-3- [1- (4-ethoxyphenyl) -1 -Fluoroethyl] phenyl} -1-deoxy-β-D-glucopyranose, ESI-MS, m / z = 609.2 ([M + 1]).

2,3,4,6-Tetra-O-acetyl-1- {4-chloro-3- [1- (4-ethoxyphenyl) -1-fluoroethyl] phenyl} -1-deoxy prepared as described above -Β-D-glucopyranose (3.98 g) was dissolved in 7 ml of anhydrous methanol containing 0.11 g of sodium methoxide, stirred at room temperature for 5 hours, and then 1 g of dry strong acidic resin was added. And stirred overnight. The resin is removed by filtration and the resulting filtrate is evaporated to dryness on a rotary evaporator to give a white solid, which is 1- {4-chloro-3-[(4-ethoxyphenyl) -1-fluoroethyl. It was phenyl} -1-deoxy-β-D-glucopyranose. ESI-MS, m / z = 441.2 ([M + 1]).
[Example 53]

  1- {4-Chloro-3- [1- (4-ethoxyphenyl) (methoxyl) methyl] phenyl} -1-deoxy-β-D-glucopyranose

A. (5-Bromo-2-chlorophenyl) (4-ethoxyphenyl) (methoxy) ethane 3.42 g of (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanol prepared according to Example 1 and 10 ml of anhydrous THF were added. Added to a 100 ml round bottom flask and the resulting solution was cooled in an ice-water bath and magnetically stirred. 0.40 g (60%) of solid NaH was added in portions, after which the resulting mixture was stirred for an additional hour before adding 1.70 g of dry MeI. The reaction mixture was stirred overnight at room temperature, carefully poured into 200 ml ice water and the pH adjusted to 4-5 with concentrated hydrochloric acid. The resulting acidic mixture was extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was (5-bromo-2-chlorophenyl) (4-Ethoxyphenyl) (methoxy) methane. ^{ESI-MS, m / z =} 355.2 ([M (79 Br) +1]), 357.2 ([M (81 Br) +1]).

B. 1- {4-Chloro-3-[(4-ethoxyphenyl) (methoxy) methyl] phenyl} -1-deoxy-β-D-glucopyranose (5-Bromo-2-chlorophenyl) ( 4-Ethoxyphenyl) (methoxy) methane 3.20 g, 10 ml anhydrous THF and a magnetic stir bar are added to a 100 ml round bottom flask, then the flask is sealed with a rubber septum and placed in an acetone-dry ice system. And cooled to -78 ° C. During stirring, 10 ml (1.0 M) n-BuLi was slowly added into the reaction mixture via syringe, after which the mixture was stirred at −78 ° C. for an additional hour. A solution of 2,3,4,6-tetra-O-trimethylsilylgluconolactone prepared according to Example 1 in 10 ml of anhydrous toluene was then slowly added by syringe into the reaction vessel. After the addition, the mixture was stirred for an additional hour and a solution of 1.92 g methanesulfonic acid in 10 ml anhydrous methanol was added via syringe, then the mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was poured into saturated NaCl solution and extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was methyl 1- {4-chloro-3 -[1- (4-Ethoxyphenyl) (methoxy) methyl] phenyl} -α / β-D-glucopyranoside. ESI-MS, m / z = 469.3 ([M + 1]).

  The resulting methyl 1- {4-chloro-3-[(4-ethoxyphenyl) (methoxy) methyl] phenyl} -α / β-D-glucopyranoside 3.63 g was dissolved in 3 ml of anhydrous dichloromethane and iced water Stir in the bath and continuously add 2 ml triethylsilane and 1 ml boron trifluoride diethyl etherate. The reaction mixture was stirred at room temperature overnight, poured carefully into 100 ml ice water, adjusted to pH = 8 with saturated sodium bicarbonate solution and extracted twice with 100 ml dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give a colorless oily product, which was 1- {4-chloro-3- [(4-Ethoxyphenyl) (methoxyl) methyl] phenyl} -α / β-D-glucopyranose. ESI-MS, m / z = 439.1 ([M + 1]).

  The resulting colorless oily product 1- {4-Chloro-3-[(4-ethoxyphenyl) (methoxy) methyl] phenyl} -α / β-D-glucopyranose 3.13 g was added to 20 ml anhydrous Dissolved in acetic acid and added 0.5 g sodium acetate anhydride. The resulting solution was magnetically stirred and heated to reflux for 1 hour. After cooling, the mixture was poured into 100 ml water, stirred at room temperature overnight and extracted twice with 100 ml dichloromethane. The combined extracts were washed once with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give an off-white solid. Colorless crystals formed after purification by silica column chromatography, which were 2,3,4,6-tetra-O-acetyl-1- {4-chloro-3-[(4-ethoxyphenyl) (methoxyl) methyl. Phenyl} -1-deoxy-β-D-glucopyranose, ESI-MS, m / z = 607.3 ([M + 1]).

2,3,4,6-Tetra-O-acetyl-1- {4-chloro-3-[(4-ethoxyphenyl) (methoxyl) methyl] phenyl} -1-deoxy-β- prepared as described above 4.10 g of D-glucopyranose is dissolved in 7 ml of anhydrous methanol containing 0.11 g of sodium methoxide, stirred at room temperature for 5 hours, then added with 1 g of dry strongly acidic resin, and at room temperature overnight. Stir. The resin is removed by filtration and the resulting filtrate is evaporated to dryness on a rotary evaporator to give a white solid, which is 1- {4-chloro-3- [1- (4-ethoxyphenyl) (methoxyl) Methyl] phenyl} -1-deoxy-β-D-glucopyranose. ESI-MS, m / z = 439.1 ([M + 1]).
[Example 54]

Dose / tablet Example 2 sample 10 mg
Microcrystalline cellulose 80mg
Pregelatinized starch 70mg
Polyvinylpyrrolidone 6mg
Sodium carboxymethyl starch 5mg
Magnesium stearate 2mg
Talc powder 2mg

The active ingredient, pregelatinized starch and microcrystalline cellulose were screened and mixed thoroughly. A polyvinylpyrrolidone solution was added and the resulting mixture was mixed and prepared into a wet mass, which was then screened to prepare wet granules and then dried at 50-60 ° C. Sodium carboxymethyl starch, magnesium stearate and talc powder were pre-screened and added into the aforementioned granules for tableting.
[Example 55]

Dose / tablet Example 1 sample 10 mg
Microcrystalline cellulose 80mg
Pregelatinized starch 70mg
Polyvinylpyrrolidone 6mg
Sodium carboxymethyl starch 5mg
Magnesium stearate 2mg
Talc powder 2mg

The active ingredient, pregelatinized starch and microcrystalline cellulose were screened and mixed thoroughly. A polyvinylpyrrolidone solution was added and the resulting mixture was mixed and prepared into a wet mass, which was then screened to prepare wet granules and then dried at 50-60 ° C. Carboxymethyl starch sodium salt, magnesium stearate and talc powder were pre-screened and added into the aforementioned granules for tableting.
[Example 56]

Dose / tablet Example 16 sample 10 mg
Microcrystalline cellulose 30mg
Pregelatinized starch 20mg
Polyvinylpyrrolidone 3mg
Magnesium stearate 2mg
Talc powder 1mg

The active ingredient, pregelatinized starch and microcrystalline cellulose were screened and mixed thoroughly. A polyvinylpyrrolidone solution was added and the resulting mixture was mixed and prepared into a wet mass, which was then screened to prepare wet granules and then dried at 50-60 ° C. Magnesium stearate and talc powder were prescreened and then added to the granules as described above and the resulting mixture was filled into capsules.
[Example 57]

Dose / tablet Example 31 sample 10 mg
Microcrystalline cellulose 30mg
Pregelatinized starch 20mg
Polyvinylpyrrolidone 3mg
Magnesium stearate 2mg
Talc powder 1mg

The active ingredient, pregelatinized starch and microcrystalline cellulose were screened and mixed thoroughly. A polyvinylpyrrolidone solution was added and the resulting mixture was mixed and prepared into a wet mass, which was then screened to prepare wet granules and then dried at 50-60 ° C. Magnesium stearate and talc powder were prescreened and then added to the granules as described above and the resulting mixture was filled into capsules.
[Example 58]

Dose / 50ml
Sample of Example 45 10 mg
Citric acid 100mg
NaOH appropriate amount (to pH 4.0-5.0)
50ml distilled water

First, citric acid was added into distilled water. Samples were added after stirring and dissolution. The solution was heated slightly to dissolve and adjusted to pH 4.0-5.0. 0.2 g of activated carbon was added and the solution was stirred for 20 minutes at room temperature and then filtered. After controlling and measuring the concentration of the filtrate, the filtrate was packed in 5 ml per ampoule and sterilized at high temperature for 30 minutes. An injection is thus obtained.
[Example 59]

Dose / 50ml
Sample of Example 46 10 mg
Citric acid 100mg
NaOH appropriate amount (to pH 4.0-5.0)
50ml distilled water

First, citric acid was added into distilled water. Samples were added after stirring and dissolution. The solution was heated slightly to dissolve and adjusted to pH 4.0-5.0. 0.2 g of activated carbon was added and the solution was stirred for 20 minutes at room temperature and then filtered. After controlling and measuring the concentration of the filtrate, the filtrate was packed in 5 ml per ampoule and sterilized at high temperature for 30 minutes. An injection is thus obtained.
[Example 60]

Sample of Example 47 3.0 g
Poloxamer 1.0g
Sodium hydroxide 0.2g
Citric acid appropriate amount mannitol 26.0g
Lactose 23.0g
100ml water for injection

Preparation process: The main drug, mannitol, lactose and poloxamer were added to 80 ml of water for injection and stirred to dissolve. 1 mol of citric acid per liter was added to adjust the pH to 7.0-9.0, and water was added to 100 ml. 0.5 g of activated carbon was added and the resulting mixture was stirred at 30 ° C. for 20 minutes before decarbonization. Bacteria were removed by filtration using a Millipore filter. The filtrate was packed at 1 ml per strip. After freezing for 2 hours, the sample was hypobaric dried for 12 hours under freezing. After returning the temperature of the sample to room temperature, the sample was further dried for 5 hours, resulting in a white brittle block that was sealed before formation was complete.
[Example 61]

Granules 100 bags Sample of Example 48 30.0 g
Lactose 55.0g
Mannitol 14.0g
Aspartame 0.05g
Essence 0.05g
2% hydroxypropylmethylcellulose (prepared with pure water)

Preparation process: The active ingredient and adjunct materials were screened through a 100 mesh screen and mixed thoroughly, then the prescribed dose of adjunct material was weighed and thoroughly mixed with the active ingredient. After the adhesive was added, the mixture was prepared into a wet mass, granulated using a 14 mesh screen, dried at 55 ° C. and screened through a 12 mesh screen. The bag was weighed and then packaged.
[Example 62]

  A suspension of 5 mg of test compound per ml was prepared by dissolving the sample in 1% sodium carboxymethylcellulose solution. The dose administered is 0.2 ml per 20 g body weight, which is equivalent to a dose of 10 mg per kg.

  Healthy ICR mice are halved and have a weight of 20-24 g according to standard level mice. The animals were fasted for 16 hours. Two hours after dosing of the test compound, 2 g / kg of glucose in saline was injected intraperitoneally (for dapagliflozin, glucose was injected 1.5 hours after dosing) and blood samples were challenged with glucose. ) Thereafter, they were collected from the tail vein of the mice using capillaries at a fixed time of 0.5 hours, 1 hour, 2 hours, 3 hours and 4 hours. Serum was separated using centrifugation. The glucose content of serum at different time points was measured using the glucose oxidase method. The results are shown in the table below.

This result suggests that all compounds can significantly improve glucose tolerance.

Claims (17)

A compound having the structure of general formula I or a pharmaceutically acceptable salt or prodrug ester thereof:

[Where:
R ¹ , R ² , R ³ and R ⁴ are H, F, Cl, Br, I, OH, OR ⁷ , SR ⁸ , OCF ₃ , CF ₃ , CHF ₂ , CH ₂ F, C ₁ -C ₃ alkyl. And cycloalkyl having 3 to 5 carbon atoms, wherein R ⁷ and R ⁸ are independently selected from C ₁ -C ₃ alkyl, said alkyl and cycloalkyl are both Or may be substituted with one or more atoms selected from F and Cl,
Ring A is selected from an aromatic monocyclic ring and an aromatic bicyclic ring, and two rings in the aromatic bicyclic ring are condensed to form a condensed ring, or are covalently bonded as two independent aromatic rings. And both the aromatic monocycle and the aromatic bicycle may be substituted with 1 to 3 heteroatoms selected from O, S and N 5 A 12-membered ring, wherein ring A is linked to the other part of compound I at any possible position;
The definitions of R ⁵ and R ⁶ are as follows:
(1) R ⁵ = R ⁶ = Me,
(2) R ⁵ = Me, R ⁶ = OMe,
(3) R ⁵ = Me, R ⁶ = H,
(4) R ⁵ = Me, R ⁶ = F,
(5) R ⁵ = F, R ⁶ = H, and (6) R ⁵ = OMe, R ⁶ = H
Selected from]. R ¹ , R ² , R ³ and R ⁴ are H, F, Cl, OR ⁷ , SR ⁸ , OCF ₃ , CF ₃ , CHF ₂ , CH ₂ F, C ₁ -C ₃ alkyl and 3-5 Independently selected from the group consisting of cycloalkyl having carbon atoms, wherein R ⁷ and R ⁸ are independently selected from C ₁ -C ₃ alkyl, wherein said alkyl and cycloalkyl are both from F and Cl Optionally substituted with one or more selected atoms,
Ring A is selected from an aromatic monocyclic ring and an aromatic bicyclic ring, and both the aromatic monocyclic ring and the aromatic bicyclic ring are substituted with 1 to 2 heteroatoms selected from O and S. A 5- to 12-membered ring, wherein ring A is linked to the other part of compound I at any possible position;
The definitions of R ⁵ and R ⁶ are as follows:
(1) R ⁵ = R ⁶ = Me,
(2) R ⁵ = Me, R ⁶ = H,
(3) R ⁵ = Me, R ⁶ = F, and (4) R ⁵ = F, R ⁶ = H
A compound having the structure of general formula I according to claim 1 or a pharmaceutically acceptable salt or prodrug ester thereof selected from: R ¹ , R ² , R ³ and R ⁴ are F, Cl, OR ⁷ , SR ⁸ , OCF ₃ , CF ₃ , CHF ₂ , CH ₂ F, C ₁ -C ₃ alkyl and 3 to 4 carbon atoms. Independently selected from the group consisting of cycloalkyl having: wherein R ⁷ and R ⁸ are independently selected from C ₁ -C ₃ alkyl, both said alkyl and cycloalkyl being one or more F May be substituted with atoms,
Ring A is a benzene ring, a benzothiophene ring, a benzofuran ring, an azulene, a benzene ring and a thiophene ring that are covalently linked in any possible form, and a benzene that is covalently linked in any possible form Selected from the group consisting of a ring and a furan ring, wherein ring A is linked to the other part of compound I at any possible position;
The definitions of R ⁵ and R ⁶ are as follows:
(1) R ⁵ = R ⁶ = Me,
(2) R ⁵ = Me, R ⁶ = H, and (3) R ⁵ = F, R ⁶ = H
A compound having the structure of general formula I according to claim 1 or 2, or a pharmaceutically acceptable salt or prodrug ester thereof, selected from: The structure of the compound is:

A compound having the structure of general formula I according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or prodrug ester thereof, selected from the structures:   A pharmaceutically acceptable prodrug ester is formed by esterifying any one or more hydroxyl groups present in the molecule with one or more of acetyl, pivaloyl, phosphoryl, carbamoyl and alkoxyformyl. A compound having the structure of general formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug ester thereof.

Wherein the base A is selected from N-methylmorpholine, triethylamine, pyridine and 4-dimethylaminopyridine, the base B is selected from sodium acetate anhydride, pyridine and 4-dimethylaminopyridine, and the base C is Selected from sodium methoxide, NaOH and KOH)
A method for preparing a compound having the structure of general formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or prodrug ester thereof, comprising the steps of: The trimethylsilylating reagent is trimethylchlorosilane, the alkyllithium reagent is n-butyllithium, the acid is selected from methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, the Lewis acid is BF ₃ .Et ₂ O, is selected from BF 3 _· MeCN and trifluoroacetic acid, the reducing agent is selected from triethylsilane and triisopropylsilane, acetylation reagent is selected from acetic anhydride and acetyl chloride, the method of claim 6. (1) When R ⁵ = R ⁶ = Me, Compound IV is IV-1

Wherein the compound IV-1 has the following pathway:

Wherein compound XVIII is treated with MeLi, MeMgI or MeMgBr to give compound XIX, which reacts with compound XII in the presence of an acid to give compound IV-1, wherein said acid is methanesulfonic acid, Or (2) when R ⁵ = Me, R ⁶ = OMe, compound IV is IV-2, which is synthesized by trifluoromethanesulfonic acid, p-toluenesulfonic acid or concentrated sulfuric acid)

Wherein the compound IV-2 has the following pathway:

[Wherein compound XIII is treated with MeLi, MeMgI or MeMgBr to give compound XX, which is treated with a methylating reagent in the presence of a base to give compound IV-2, said base being NaH , KH or NaNH ₂ and the methylating reagent is Me ₂ SO ₄ or MeI,
Alternatively, the compound XX can have the following route:

Embedded image wherein compound XIV is synthesized by treatment with n-BuLi or metallic Mg to yield compound XV, which reacts with compound XXI to yield compound XX), or ( 3) When R ⁵ = Me, R ⁶ = H, compound IV is IV-3

Wherein the compound IV-3 has the following pathway:

(In the formula, compound XX is reduced to compound IV-3 by reduction with a reducing agent in the presence of an acid, and the acid is BF ₃ .Et ₂ O or trifluoroacetic acid, and the reducing agent is triethylsilane or triethylsilane. Or (4) when R ⁵ = Me, R ⁶ = F, compound IV is IV-4

Wherein the compound IV-4 has the following pathway:

(Wherein compound XX reacts with a fluorinating agent to give compound IV-4, said fluorinating agent being SF ₄ or Et ₂ NSF ₃ ) or (5) R ⁵ = F, When R ⁶ = H, compound IV is IV-5

Wherein the compound IV-5 has the following pathway:

(Wherein compound XVII reacts with a fluorinating agent to yield compound IV-5, said fluorinating agent is SF ₄ or Et ₂ NSF ₃ and said compound XVII reduces compound XIII by the following reaction: And the reducing agent is selected from NaBH ₄ , KBH ₄ , LiAlH ₄ and LiBH ₄ )

Or (6) when R ⁵ = OMe, R ⁶ = H, compound IV is IV-6

Wherein the compound IV-6 has the following pathway:

(Wherein compound XVII is treated with a methylating reagent in the presence of a base to give compound IV-6, wherein the base is NaH, KH or NaNH ₂ and the methylating reagent is Me ₂ SO ₄ or MeI. The method according to claim 6 or 7, wherein

The method according to claim 6, comprising the steps of:   A compound having the structure of general formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or prodrug ester thereof, or a method according to any one of claims 6 to 9. Or a pharmaceutically acceptable salt or prodrug ester thereof in the inhibition of sodium-glucose cotransporter 2.   A compound having the structure of general formula I according to any one of claims 1 to 5 and a pharmaceutically acceptable salt or prodrug ester thereof, or a method according to any one of claims 6 to 9. Or a pharmaceutically acceptable salt or prodrug ester thereof in the treatment of diabetes.   A compound having the structure of general formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or prodrug ester thereof, or a method according to any one of claims 6 to 9. Or a pharmaceutically acceptable salt or prodrug ester thereof in the preparation of a sodium-glucose cotransporter 2 inhibitor.   A compound having the structure of general formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or prodrug ester thereof, or a method according to any one of claims 6 to 9. Or a pharmaceutically acceptable salt or prodrug ester thereof in the preparation of a medicament for treating diabetes.   An effective amount of a compound having the structure of general formula I according to any of claims 1 to 5, or a pharmaceutically acceptable salt or prodrug ester thereof, or according to any of claims 6 to 9. A method of treating diabetes comprising administering to a patient a compound having the structure of general formula I prepared by the method or a pharmaceutically acceptable salt or prodrug ester thereof.   A compound having the structure of general formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or prodrug ester thereof, or a method according to any one of claims 6 to 9. A pharmaceutical composition comprising a compound having the structure of the general formula I or a pharmaceutically acceptable salt or prodrug ester thereof and a pharmaceutically acceptable carrier and / or excipient.   The pharmaceutical composition according to claim 15, which is a solid oral preparation, liquid oral preparation or injectable preparation. Solid oral preparations and liquid oral preparations include dispersed tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, granules, and oral solutions, and injection preparations are vial injections, frozen for injection. 17. A pharmaceutical composition according to claim 16, comprising a dry powder, a large volume infusion and a small volume infusion.